Multifunctional low-density lipoprotein nanoplatforms

多功能低密度脂蛋白纳米平台

• 批准号: 7245112
• 负责人: GANG ZHENG
• 金额: $ 15万
• 依托单位: UNIVERSITY HEALTH NETWORK
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-12 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7245112
• 关键词: Affinity; Anatomy; Applications Grants; Binding; Biocompatible; Blood Circulation; Cancer Detection; Cells; Cholesterol; Detection; Fluorescent Probes; Folic Acid; Gadolinium DTPA; Gadopentetate Dimeglumine; Goals; Label; Lipids; Lipoproteins; Low Density Lipoprotein Receptor; Low-Density Lipoproteins; Magnetic Resonance Imaging; Malignant Neoplasms; Modification; Nanostructures; Pathway interactions; Phase; Phospholipids; Photochemotherapy; Resolution; Reticuloendothelial System; Signal Transduction; Solutions; Specificity; Surface; Testing; Toxic effect; apolipoprotein B-100; base; biomaterial compatibility; cancer cell; concept; design; folate-binding protein; imaging probe; immunogenic; monolayer; nanodevice; novel; particle; prototype; receptor binding; scavenger receptor; tumor

DESCRIPTION (provided by applicant): Lipoproteins are naturally-existing nanostructures (8 - 1000 nm) responsible for the transport of cholesterol and other lipids in the blood circulation. Being endogenous carriers, lipoproteins are not immunogenic and escape recognition by the reticuloendothelial system. This project will initiate a broad exploration of lipoprotein particles as diverse and biocompatible nanoplatforms, focusing on low-density lipoprotein (LDL) (22nm) as a prototype. In our multifunctional LDL-based nanoplatform (LBNP) design, the diverse targeting is achieved by conjugating certain tumor-homing molecules to the receptor-binding Lys residues exposed on the apoB-100 surface of LDL. This turns off the LDL receptor (LDLR) binding and redirects the resulting LBNP to cancer cells or tumor vasculature via other cancer signatures. The LBNP multifunctionality is achieved by incorporating near-infrared fluorescent (NIRF)/photodynamic therapy (PDT) agents and magnetic resonance imaging (MRI) probes, respectively, into the LBNP lipid core and on its phospholipids monolayer. Thus, accumulation of the MRI/NIRF probes in target cells provides a facile mechanism for amplification of the MRI/NIRF detectable signal and affords opportunities to combine the strength of both MRI (high resolution/anatomic) and NIRF (high sensitivity), whereas the selective delivery of PDT agents to tumors via these pathways also provides a facile transition between cancer detection and treatment. During the R21 phase of the grant proposal (year 01), proof-of-feasibility of the LBNP concept will be provided by conjugating folic acid to LDL to achieve high affinity toward the folate receptor. In the R33 phase (year 02 to 04), the goal is to demonstrate the binding specificity of LBNP to folate receptors and to bring new functions to the LBNP particles thereby generating two novel folate receptor-targeted nanodevices: NIR dyereconstituted LBNP for NIRF/PDT and Gd-DTPA labeled LBNP for MRI. The key questions that will be tested are: 1) Will the stability of LDL particles be compromised by the proposed LDL modifications? 2) Can folic acid-conjugated LBNP bind to folate receptor specifically without binding to LDLR and/or LDL-scavenger receptor? 3) Can folate receptor binding affinity of LBNP be maximized using the multivalency effect? 4) Can the LBNP payload be high enough to exceed the intracellular MRI detection limit? This approach is expected to generate non-immunogenic multifunctional lipoprotein nanoplatforms, thus providing a solution to common problems associated with most synthetic nanodevices, namely biocompatibility and toxicity issues.

描述（由申请人提供）：